Molecular mechanisms of oestrogen action on growth of human breast cancer cells in culture

Abstract

Growth responses to oestrogen can be reproducibly obtained using a selection of oestrogen-receptor-containing human breast cancer cell lines, and molecular mechanisms have been shown to include modulation to growth factor/receptor/signalling pathways, cell-cycle proteins, apoptosis, differentiation, adhesion, motility and migration. Considerable progress has been made in understanding the molecular basis of oestrogen action on gene expression through the ligand-activated transcription factors human oestrogen receptor α (ERα) and ERβ and the resulting effects on global gene expression patterns, but the full profile of coordination of the alterations, which brings about changes in cell growth through genomic and non-genomic mechanisms remain to be fully elucidated. Oestrogen regulation of cell growth involves a complex cross-talk between oestrogen receptor and growth factor signalling pathways such that inhibition of one pathway may lead to stimulation of another, which may explain the remarkable ability of human breast cancer cells to escape from any mode of imposed growth inhibition be it oestrogen deprivation or administration of antioestrogen. Although studies on cell growth have focused to date on the effects of physiological oestrogens, many hundreds of environmental chemicals with oestrogenic properties have now been measured in the human breast. Whether or not the weight of evidence eventually establishes any causal link of complex mixtures of environmental oestrogenic chemicals with breast cancer, the presence of so many oestrogenic chemicals in the breast must influence resulting oestrogenic responses, and the impact of this additional oestrogenic burden needs to be taken into account in future studies on growth regulation of human breast cancer cells.

Enhanced sensitivity to rapamycin following long-term oestrogen deprivation in MCF-7, T-47-D and ZR-75-1 human breast cancer cells

“…The oestrogen deprivation cell culture model MCF-7 McGrath human breast cancer cells (Osborne et al 1987) are dependent on oestrogen for growth such that if they are grown in phenol red-free medium with DC-FCS, then cell proliferation is low in the absence of added oestrogen and is stimulated by E 2 (Darbre & Daly 1989). The T-47-D and ZR-75-1 human breast cancer cells are similarly responsive to oestrogen for growth (Darbre & Daly 1989).…”

“…The T-47-D and ZR-75-1 human breast cancer cells are similarly responsive to oestrogen for growth (Darbre & Daly 1989). However, after long-term maintenance under oestrogen-deprived conditions in the phenol red-free medium with DC-FCS, these cells can all adapt and learn to grow such that their growth rate eventually rises to equal that of the previous growth rate only in the presence of E 2 .…”

“…Stock culture of oestrogen-maintained MCF-7 cells MCF-7 McGrath human breast cancer cells were kindly provided by Osborne et al (1987) at passage number 390 and these cells are dependent on oestrogen for growth (Darbre & Daly 1989). These MCF-7 cells were grown in our laboratory as monolayer cultures in DMEM (containing phenol red) (Invitrogen) supplemented with 5% (v/v) FCS (Invitrogen), 10 mg/ml insulin (Sigma) and 10 K8 M E 2 (Steraloids, Croydon, UK) in a humidified atmosphere of 10% carbon dioxide in air at 37 8C.…”

“…The ZR-75-1 cells are dependent on oestrogen for their growth (Darbre et al 1983, Darbre & Daly 1989. The T-47-D cells are responsive rather than dependent on oestrogen for their growth in that they can proliferate in the absence of oestrogen but their growth rate can be increased by addition of E 2 (Darbre & Daly 1989). These cells were grown as described above for MCF-7 cells but the medium lacked any insulin.…”

Environmental oestrogens and breast cancer: long-term low-dose effects of mixtures of various chemical combinations

“…Environmental oestrogens have challenged classical concepts of toxicology because of their ability to act through receptor-mediated, cell signalling or enzymatic mechanisms which can result in targeted action at low doses 24. Studies in vitro have shown that, although these compounds bind to oestrogen receptors with a lower relative binding affinity (RBA) than oestradiol, their efficacy is not low if a sufficient quantity is present 7 16.…”